Cyclopropylamines as lsd1 inhibitors

ABSTRACT

The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

FIELD OF THE INVENTION

The present invention relates to enzyme inhibitors, which selectivelymodulate demethylase, and uses therefor. Particular embodimentscontemplate compounds and disease indications amenable to treatment bymodulation of lysine specific demethylase-1 (LSD1).

BACKGROUND OF THE INVENTION

Epigenetic modifications can impact genetic variation but, whendysregulated, can also contribute to the development of various diseases(Portela, A. and M. Esteller, Epigenetic modifications and humandisease. Nat Biotechnol, 2010. 28(10): p. 1057-68; Lund, A. H. and M.van Lohuizen, Epigenetics and cancer. Genes Dev, 2004. 18(19): p.2315-35). Recently, in depth cancer genomics studies have discoveredmany epigenetic regulatory genes are often mutated or their ownexpression is abnormal in a variety of cancers (Dawson, M. A. and T.Kouzarides, Cancer epigenetics: from mechanism to therapy. Cell, 2012.150(1): p. 12-27; Waldmann, T. and R. Schneider, Targeting histonemodifications—epigenetics in cancer. Curr Opin Cell Biol, 2013. 25(2):p. 184-9; Shen, H. and P. W. Laird, Interplay between the cancer genomeand epigenome. Cell, 2013. 153(1): p. 38-55). This implies epigeneticregulators function as cancer drivers or are permissive fortumorigenesis or disease progression. Therefore, deregulated epigeneticregulators are attractive therapeutic targets.

One particular enzyme which is associated with human diseases is lysinespecific demethylase-1 (LSD1), the first discovered histone demethylase(Shi, Y., et al., Histone demethylation mediated by the nuclear amineoxidase homolog LSD1. Cell, 2004. 119(7): p. 941-53). It consists ofthree major domains: the N-terminal SWIRM which functions in nucleosometargeting, the tower domain which is involved in protein-proteininteraction, such as transcriptional co-repressor, co-repressor ofRE1-silencing transcription factor (CoREST), and lastly the C terminalcatalytic domain whose sequence and structure share homology with theflavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e.,MAO-A and MAO-B) (Forneris, F., et al., Structural basis of LSD1-CoRESTselectivity in histone H3 recognition. J Biol Chem, 2007. 282(28): p.20070-4; Anand, R. and R. Marmorstein, Structure and mechanism oflysine-specific demethylase enzymes. J Biol Chem, 2007. 282(49): p.35425-9; Stavropoulos, P., G. Blobel, and A. Hoelz, Crystal structureand mechanism of human lysine-specific demethylase-1. Nat Struct MolBiol, 2006. 13(7): p. 626-32; Chen, Y., et al., Crystal structure ofhuman histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad SciUSA, 2006. 103(38): p. 13956-61). LSD1 also shares a fair degree ofhomology with another lysine specific demethylase (LSD2) (Karytinos, A.,et al., A novel mammalian flavin-dependent histone demethylase. J BiolChem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism ofaction is conserved in two isoforms, the substrate specificities arethought to be distinct with relatively small overlap. The enzymaticreactions of LSD1 and LSD2 are dependent on the redox process of FAD andthe requirement of a protonated nitrogen in the methylated lysine isthought to limit the activity of LSD1/2 to mono- and di-methylated atthe position of 4 or 9 of histone 3 (H3K4 or H3K9). These mechanismsmake LSD1/2 distinct from other histone demethylase families (i.e.Jumonji domain containing family) that can demethylate mono-, di-, andtri-methylated lysines through alpha-ketoglutarate dependent reactions(Kooistra, S. M. and K. Helin, Molecular mechanisms and potentialfunctions of histone demethylases. Nat Rev Mol Cell Biol, 2012. 13(5):p. 297-311; Mosammaparast, N. and Y. Shi, Reversal of histonemethylation: biochemical and molecular mechanisms of histonedemethylases. Annu Rev Biochem, 2010. 79: p. 155-79).

Methylated histone marks on K3K4 and H3K9 are generally coupled withtranscriptional activation and repression, respectively. As part ofcorepressor complexes (e.g., CoREST), LSD1 has been reported todemethylate H3K4 and repress transcription, whereas LSD1, in nuclearhormone receptor complex (e.g., androgen receptor), may demethylate H3K9to activate gene expression (Metzger, E., et al., LSD1 demethylatesrepressive histone marks to promote androgen-receptor-dependenttranscription. Nature, 2005. 437(7057): p. 436-9; Kahl, P., et al.,Androgen receptor coactivators lysine-specific histone demethylase 1 andfour and a half LIM domain protein 2 predict risk of prostate cancerrecurrence. Cancer Res, 2006. 66(23): p. 11341-7). This suggests thesubstrate specificity of LSD1 can be determined by associated factors,thereby regulating alternative gene expressions in a context dependentmanner. In addition to histone proteins, LSD1 may demethylatenon-histone proteins. These include p53 (Huang, J., et al., p53 isregulated by the lysine demethylase LSD1. Nature, 2007. 449(7158): p.105-8.), E2F (Kontaki, H. and I. Talianidis, Lysine methylationregulates E2F1-induced cell death. Mol Cell, 2010. 39(1): p. 152-60),STAT3 (Yang, J., et al., Reversible methylation of promoter-bound STAT3by histone-modifying enzymes. Proc Natl Acad Sci USA, 2010. 107(50): p.21499-504), Tat (Sakane, N., et al., Activation of HIV transcription bythe viral Tat protein requires a demethylation step mediated bylysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog, 2011. 7(8): p.e1002184), and myosin phosphatase target subunit 1 (MYPT1) (Cho, H. S.,et al., Demethylation of RB regulator MYPT1 by histone demethylase LSD1promotes cell cycle progression in cancer cells. Cancer Res, 2011.71(3): p. 655-60). The lists of non-histone substrates are growing withtechnical advances in functional proteomics studies. These suggestadditional oncogenic roles of LSD1 beyond in regulating chromatinremodeling. LSD1 also associates with other epigenetic regulators, suchas DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysinedemethylase LSD1 (KDM1) is required for maintenance of global DNAmethylation. Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases(HDACs) complexes (Hakimi, M. A., et al., A core-BRAF35 complexcontaining histone deacetylase mediates repression of neuronal-specificgenes. Proc Natl Acad Sci USA, 2002. 99(11): p. 7420-5; Lee, M. G., etal., Functional interplay between histone demethylase and deacetylaseenzymes. Mol Cell Biol, 2006. 26(17): p. 6395-402; You, A., et al.,CoREST is an integral component of the CoREST-human histone deacetylasecomplex. Proc Natl Acad Sci USA, 2001. 98(4): p. 1454-8). Theseassociations augment the activities of DNMT or HDACs. LSD1 inhibitorsmay therefore potentiate the effects of HDAC or DNMT inhibitors. Indeed,preclinical studies have shown such potential already (Singh, M. M., etal., Inhibition of LSD1 sensitizes glioblastoma cells to histonedeacetylase inhibitors. Neuro Oncol, 2011. 13(8): p. 894-903; Han, H.,et al., Synergistic re-activation of epigenetically silenced genes bycombinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One,2013. 8(9): p. e75136).

LSD1 has been reported to contribute to a variety of biologicalprocesses, including cell proliferation, epithelial-mesenchymaltransition (EMT), and stem cell biology (both embryonic stem cells andcancer stem cells) or self-renewal and cellular transformation ofsomatic cells (Chen, Y., et al., Lysine-specific histone demethylase 1(LSD1): A potential molecular target for tumor therapy. Crit RevEukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histonedemethylase LSD1 regulates neural stem cell proliferation. Mol CellBiol, 2010. 30(8): p. 1997-2005; Adamo, A., M. J. Barrero, and J. C.Izpisua Belmonte, LSD1 and pluripotency: a new player in the network.Cell Cycle, 2011. 10(19): p. 3215-6; Adamo, A., et al., LSD1 regulatesthe balance between self-renewal and differentiation in human embryonicstem cells. Nat Cell Biol, 2011. 13(6): p. 652-9). In particular, cancerstem cells or cancer initiating cells have some pluripotent stem cellproperties that contribute the heterogeneity of cancer cells. Thisfeature may render cancer cells more resistant to conventionaltherapies, such as chemotherapy or radiotherapy, and then developrecurrence after treatment (Clevers, H., The cancer stem cell: premises,promises and challenges. Nat Med, 2011. 17(3): p. 313-9; Beck, B. and C.Blanpain, Unravelling cancer stem cell potential. Nat Rev Cancer, 2013.13(10): p. 727-38). LSD1 was reported to maintain an undifferentiatedtumor initiating or cancer stem cell phenotype in a spectrum of cancers(Zhang, X., et al., Pluripotent Stem Cell Protein Sox2 ConfersSensitivity to LSD1 Inhibition in Cancer Cells. Cell Rep, 2013. 5(2): p.445-57; Wang, J., et al., Novel histone demethylase LSD1 inhibitorsselectively target cancer cells with pluripotent stem cell properties.Cancer Res, 2011. 71(23): p. 7238-49). Acute myeloid leukemias (AMLs)are an example of neoplastic cells that retain some of their lessdifferentiated stem cell like phenotype or leukemia stem cell (LSC)potential. Analysis of AML cells including gene expression arrays andchromatin immunoprecipitation with next generation sequencing (ChIP-Seq)revealed that LSD1 may regulate a subset of genes involved in multipleoncogenic programs to maintain LSC (Harris, W. J., et al., The histonedemethylase KDMJA sustains the oncogenic potential of MLL-AF9 leukemiastem cells. Cancer Cell, 2012. 21(4): p. 473-87; Schenk, T., et al.,Inhibition of the LSD1 (KDMJA) demethylase reactivates theall-trans-retinoic acid differentiation pathway in acute myeloidleukemia. Nat Med, 2012. 18(4): p. 605-11). These findings suggestpotential therapeutic benefit of LSD1 inhibitors targeting cancershaving stem cell properties, such as AMLs.

Overexpression of LSD1 is frequently observed in many types of cancers,including bladder cancer, NSCLC, breast carcinomas, ovary cancer,glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing'ssarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostatecancer, esophageal squamous cell carcinoma, and papillary thyroidcarcinoma. Notably, studies found over-expression of LSD1 wassignificantly associated with clinically aggressive cancers, forexample, recurrent prostate cancer, NSCLC, glioma, breast, colon cancer,ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma. Inthese studies, either knockdown of LSD1 expression or treatment withsmall molecular inhibitors of LSD1 resulted in decreased cancer cellproliferation and/or induction of apoptosis. See, e.g., Hayami, S., etal., Overexpression of LSD1 contributes to human carcinogenesis throughchromatin regulation in various cancers. Int J Cancer, 2011. 128(3): p.574-86; Lv, T., et al., Over-expression of LSD1 promotes proliferation,migration and invasion in non-small cell lung cancer. PLoS One, 2012.7(4): p. e35065; Serce, N., et al., Elevated expression of LSD1(Lysine-specific demethylase 1) during tumour progression frompre-invasive to invasive ductal carcinoma of the breast. BMC ClinPathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific demethylase 1(LSD1) is highly expressed in ER-negative breast cancers and a biomarkerpredicting aggressive biology. Carcinogenesis, 2010. 31(3): p. 512-20;Konovalov, S. and I. Garcia-Bassets, Analysis of the levels oflysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors andthe effects of chemical LSD1 inhibitors in ovarian cancer cell lines. JOvarian Res, 2013. 6(1): p. 75; Sareddy, G. R., et al., KDM1 is a noveltherapeutic target for the treatment of gliomas. Oncotarget, 2013. 4(1):p. 18-28; Ding, J., et al., LSD1-mediated epigenetic modificationcontributes to proliferation and metastasis of colon cancer. Br JCancer, 2013. 109(4): p. 994-1003; Bennani-Baiti, I. M., et al.,Lysine-specific demethylase 1 (LSD1/KDM1A/A0F2/BHC110) is expressed andis an epigenetic drug target in chondrosarcoma, Ewing's sarcoma,osteosarcoma, and rhabdomyosarcoma. Hum Pathol, 2012. 43(8): p. 1300-7;Schulte, J. H., et al., Lysine-specific demethylase 1 is stronglyexpressed in poorly differentiated neuroblastoma: implications fortherapy. Cancer Res, 2009. 69(5): p. 2065-71; Crea, F., et al., Theemerging role of histone lysine demethylases in prostate cancer. MolCancer, 2012. 11: p. 52; Suikki, H. E., et al., Genetic alterations andchanges in expression of histone demethylases in prostate cancer.Prostate, 2010. 70(8): p. 889-98; Yu, Y., et al., High expression oflysine-specific demethylase 1 correlates with poor prognosis of patientswith esophageal squamous cell carcinoma. Biochem Biophys Res Commun,2013. 437(2): p. 192-8; Kong, L., et al., Immunohistochemical expressionof RBP2 and LSD1 in papillary thyroid carcinoma. Rom J Morphol Embryol,2013. 54(3): p. 499-503.

Recently, the induction of CD86 expression by inhibiting LSD1 activitywas reported (Lynch, J. T., et al., CD86 expression as a surrogatecellular biomarker for pharmacological inhibition of the histonedemethylase lysine-specific demethylase 1. Anal Biochem, 2013. 442(1):p. 104-6). CD86 expression is a marker of maturation of dendritic cells(DCs) which are involved in antitumor immune response. Notably, CD86functions as a co-stimulatory factor to activate T cell proliferation(Greaves, P. and J. G. Gribben, The role of B7 family molecules inhematologic malignancy. Blood, 2013. 121(5): p. 734-44; Chen, L. and D.B. Flies, Molecular mechanisms of T cell co-stimulation andco-inhibition. Nat Rev Immunol, 2013. 13(4): p. 227-42).

In addition to playing a role in cancer, LSD1 activity has also beenassociated with viral pathogenesis. Particularly, LSD1 activity appearsto be linked with viral replications and expressions of viral genes. Forexample, LSD1 functions as a co-activator to induce gene expression fromthe viral immediate early genes of various type of herpes virusincluding herpes simplex virus (HSV), varicella zoster virus (VZV), andβ-herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting theJMJD2 histone demethylases to epigenetically control herpesvirusinfection and reactivation from latency. Sci Transl Med, 2013. 5(167):p. 167ra5; Liang, Y., et al., Inhibition of the histone demethylase LSD1blocks alpha-herpesvirus lytic replication and reactivation fromlatency. Nat Med, 2009. 15(11): p. 1312-7). In this setting, a LSD1inhibitor showed antiviral activity by blocking viral replication andaltering virus associated gene expression.

Recent studies have also shown that the inhibition of LSD1 by eithergenetic depletion or pharmacological intervention increased fetal globingene expression in erythroid cells (Shi, L., et al., Lysine-specificdemethylase 1 is a therapeutic target for fetal hemoglobin induction.Nat Med, 2013. 19(3): p. 291-4; Xu, J., et al., Corepressor-dependentsilencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad SciUSA, 2013. 110(16): p. 6518-23). Inducing fetal globin gene would bepotentially therapeutically beneficial for the disease ofβ-globinopathies, including β-thalassemia and sickle cell disease wherethe production of normal β-globin, a component of adult hemoglobin, isimpaired (Sankaran, V. G. and S. H. Orkin, The switch from fetal toadult hemoglobin. Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643;Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetalhemoglobin: prospects for new therapies for the beta-globin disorders.Blood, 2012. 120(15): p. 2945-53). Moreover, LSD1 inhibition maypotentiate other clinically used therapies, such as hydroxyurea orazacitidine. These agents may act, at least in part, by increasingγ-globin gene expression through different mechanisms.

In summary, LSD1 contributes to tumor development by altering epigeneticmarks on histones and non-histone proteins. Accumulating data havevalidated that either genetic depletion or pharmacological interventionof LSD1 normalizes altered gene expressions, thereby inducingdifferentiation programs into mature cell types, decreasing cellproliferation, and promoting apoptosis in cancer cells. Therefore, LSD1inhibitors alone or in combination with established therapeutic drugswould be effective to treat the diseases associated with LSD1 activity.

SUMMARY OF THE INVENTION

The present invention is directed to, inter alia, a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound of Formula I and at least onepharmaceutically acceptable carrier.

The present invention is further directed to a method of inhibiting LSD1comprising contacting the LSD1 with a compound of Formula I.

The present invention is further directed to a method of treating anLSD1-mediated disease in a patient comprising administering to thepatient a therapeutically effective amount of a compound of Formula I.

DETAILED DESCRIPTION

The present invention provides, inter alia, LSD1-inhibiting compoundssuch as a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl having carbon and 1, 2,3 or 4 heteroatoms selected from N, O, and S;

ring B is 4-10 membered heterocycloalkyl having carbon and 1, 2, or 3heteroatoms selected from N, O, and S;

ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) afused bicyclic moiety having Formula (A):

wherein:

-   -   ring C1 is phenyl or 5-6 membered heteroaryl having carbon and        1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring C2 is (1) phenyl, (2) C₅₋₆ cycloalkyl, (3) 5-6 membered        heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected        from N, O, and S, or (4) 5-6 membered heterocycloalkyl having        carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

wherein said fused bicyclic moiety of Formula A is bonded to ring B viaring C1, and wherein Ring C substituents R³ and R⁴ are substituted oneither or both of C1 and C2;

wherein ring C is substituted on any ring-forming atom of ring B exceptthe ring-forming atom of ring B to which R^(Z) is bonded;

each R¹ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C14alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), C(═NR^(c))R^(b), C(═NR^(c))NR^(c)R^(d),NR^(c)C(═NR^(c))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), andS(O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(c))NR^(c)R^(d), NR^(c)C(═NR^(c))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

each R² is independently selected from halo, C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(c1))NR^(c1)R^(d1), NR^(c1)C(═NR^(c1))NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1);

wherein each R² is substituted on any ring-forming atom of ring B exceptthe ring-forming atom of ring B to which R^(Z) is bonded;

each R³ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(c2))R^(b2),C(═NR^(c2))NR^(c2)R^(d2), NR^(c2)C(═NR^(c2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(c2))NR^(c2)R^(d2),NR^(c2)C(═NR^(c2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R⁴ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3) NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(c3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3) S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3)OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

R⁵ and R⁶ are each independently selected from H, halo, CN, C₁₋₄ alkyl,C₁₋₄ cyanoalkyl, C₁₋₄ haloalkyl, and —(C₁₋₄ alkyl)-OR^(a);

R^(Z) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4) OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4) NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4) NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4)NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(a), R^(b), R^(c), R^(d), R^(a2), R^(b2), R^(c2), R^(d2), R^(a3),R^(b3), R^(c3), R^(d3), R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃-cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ cycanoalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c) and R^(d) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

-   -   or any R^(c4) and R^(d4) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),        C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),        NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NRSC(O)NR^(c5)R^(d5),        NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), and        S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁-4 cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),        C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),        NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),        NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), and        S(O)₂NR^(c5)R^(d5);

each R^(a1), R^(b1), R^(c1), R^(d1) is independently selected from H andC₁₋₆ alkyl optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;and

each R^(e), R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is independentlyselected from H, C₁₋₄ alkyl, and CN;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 0, 1, 2, or 3; and

q is 0 or 1.

In some embodiments, ring B is monocyclic 4-7 membered heterocycloalkylhaving carbon and 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, ring B is a 4-10 membered heterocycloalkyl havingcarbon and 1, 2, or 3 heteroatoms selected from N, O, and S wherein saidring B comprises at least one ring-forming N atom.

In some embodiments, ring B is a 4-7 membered heterocycloalkyl havingcarbon and 1, 2, or 3 heteroatoms selected from N, O, and S wherein saidring B comprises at least one ring-forming N atom.

In some embodiments, ring B is a 6-membered heterocycloalkyl ring havingcarbon and 1 or 2 heteroatoms selected from N, O, and S wherein saidring B comprises at least one ring-forming N atom.

In some embodiments, ring B is azetidine or piperidine.

In some embodiments, ring B is azetidine.

In some embodiments, ring B is piperidine.

In some embodiments, ring C is bound to a ring-forming N atom of ring B.

In some embodiments, ring A is C₆₋₁₀ aryl or 5-10 membered heteroarylhaving carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring B is 4-10 membered heterocycloalkyl havingcarbon and 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, ring C is (1) phenyl, (2) monocyclic 5-6 memberedheteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N,O, and S, or (3) a fused bicyclic moiety having Formula (A):

wherein:

-   -   ring C1 is phenyl or 5-6 membered heteroaryl having carbon and        1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring C2 is (1) phenyl, (2) C₅₋₆ cycloalkyl, (3) 5-6 membered        heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected        from N, O, and S, or (4) 5-6 membered heterocycloalkyl having        carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, the compounds of the invention include a compoundof Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl having carbon and 1, 2,3 or 4 heteroatoms selected from N, O, and S;

ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) afused bicyclic moiety having Formula (A):

wherein:

-   -   ring C1 is phenyl or 5-6 membered heteroaryl having carbon and        1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring C2 is (1) phenyl, (2) C₅₋₆ cycloalkyl, (3) 5-6 membered        heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected        from N, O, and S, or (4) 5-6 membered heterocycloalkyl having        carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

wherein said fused bicyclic moiety of Formula A is bonded to ring B viaring C1, and wherein Ring C substituents R³ and R⁴ are substituted oneither or both of C1 and C2;

X is —CH₂— or —CH₂—CH₂—;

Y is —CH₂— or —CH₂—CH₂—;

each R¹ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆-10 aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), andS(O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

each R² is independently selected from halo, C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NRlRdl, NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

wherein each R² is substituted any ring-forming carbon atom of the ringin Formula II containing X and Y except the ring-forming carbon atom towhich R^(Z) is bonded;

each R³ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R⁴ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3) S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

R⁵ and R⁶ are each independently selected from H, halo, CN, C₁₋₄ alkyl,C₁₋₄ cyanoalkyl, C₁₋₄ haloalkyl, and —(C₁₋₄ alkyl)-OR^(a5);

R^(Z) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4S)(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4) NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4)NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

-   -   each R^(a), R^(b), R^(c), R^(d), R^(a2), R^(b2), R^(c2), R^(d2),        R^(a3), R^(b3), R^(c3), R^(d3), R^(a4), R^(b4), R^(c4), and        R^(d4) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1,        2, 3, 4, or 5 substituents independently selected from C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cycanoalkyl, halo, CN, OR^(a5),        SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),        NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),        C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),        S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),        NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

or any R^(c) and R^(d) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NRSC(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-6 membered heteroaryl are optionally substituted by 1,2, or 3 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5)C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

-   -   each R^(a1), R^(b1), R^(c1), R^(d1) is independently selected        from H and C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4, or        5 substituents independently selected from halo, CN, OR^(a5),        SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),        NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),        C(═NR^(e5))NR^(c5)R^(d5), NR^(c)C(═NR^(e))NR^(c5)R^(d5),        S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),        NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;and

each R^(e), R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is independentlyselected from H, C₁₋₄ alkyl, and CN;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 0, 1, 2, or 3; and

q is 0 or 1.

In some embodiments, the compounds of the invention include a compoundof Formula IIIa or IIIb:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl having carbon and 1, 2,3 or 4 heteroatoms selected from N, O, and S;

ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) afused bicyclic moiety having Formula (A):

wherein:

-   -   ring C1 is phenyl or 5-6 membered heteroaryl having carbon and        1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring C2 is (1) phenyl, (2) C₅₋₆ cycloalkyl, (3) 5-6 membered        heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected        from N, O, and S, or (4) 5-6 membered heterocycloalkyl having        carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

wherein said fused bicyclic moiety of Formula A is bonded to ring B viaring C1, and wherein Ring C substituents R³ and R⁴ are substituted oneither or both of C1 and C2;

each R¹ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), andS(O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

each R² is independently selected from halo, C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1);

wherein each R² is substituted on any ring-forming carbon atom of theazetidine ring depicted in in Formula IIIa or the piperidine ringdepicted in Formula IIIb except the ring-forming carbon atom to whichR^(Z) is bonded;

each R³ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a2), SR^(a), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R⁴ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3) S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

R⁵ and R⁶ are each independently selected from H, halo, CN, C₁₋₄ alkyl,C₁₋₄ cyanoalkyl, C₁₋₄ haloalkyl, and —(C₁₋₄ alkyl)-OR^(a5);

R^(Z) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4S)(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4) NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4)NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

-   -   each R^(a), R^(b), R^(c), R^(d), R^(a2), R^(b2), R^(c2), R^(d2),        R^(a3), R^(b3), R^(c3), R^(d3), R^(a4), R^(b4), R^(c4), and        R^(d4) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1,        2, 3, 4, or 5 substituents independently selected from C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cycanoalkyl, halo, CN, OR^(a5),        SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),        NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),        C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),        S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),        NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

or any R^(c) and R^(d) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NRSC(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-6 membered heteroaryl are optionally substituted by 1,2, or 3 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

-   -   or any R^(c4) and R^(d4) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),        C(O)NR^(c5)R^(d5)C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),        NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),        NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), and        S(O)₂NR^(c5)R^(d), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),        C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),        NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),        NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), and        S(O)₂NR^(c5)R^(d5);

each R^(a1), R^(b1), R^(c1), R^(d1) is independently selected from H andC₁₋₆ alkyl optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;and

each R^(e), R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is independentlyselected from H, C₁₋₄ alkyl, and CN;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 0, 1, 2, or 3; and

q is 0 or 1.

In some embodiments, the compounds of the invention include a compoundof Formula IVa or IVb:

In some embodiments, the compounds of the invention include a compoundof Formula Va or Vb:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl having carbon and 1, 2,3 or 4 heteroatoms selected from N, O, and S;

ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) afused bicyclic moiety having Formula (A):

wherein:

-   -   ring C1 is phenyl or 5-6 membered heteroaryl having carbon and        1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring C2 is (1) phenyl, (2) C₅₋₆ cycloalkyl, (3) 5-6 membered        heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected        from N, O, and S, or (4) 5-6 membered heterocycloalkyl having        carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   wherein said fused bicyclic moiety of Formula A is bonded to        ring B via ring C1, and wherein ring C substituents R³ and R⁴        are substituted on either or both of C1 and C2;

each R¹ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), andS(O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

each R³ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2) NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a2), SR^(a), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)R^(d2) NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R⁴ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3) NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3) S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3)OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3)S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R^(a), R^(b), R^(c), R^(d), R^(a2), R^(b2), R^(c2), R^(d2), R^(a3),R^(b3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cycanoalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c) and R^(d) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5) S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(as), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

-   -   each R^(a5), R^(b5), R^(c5), and R^(d5) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; and

each R^(e), R^(e2), R^(e3), and R^(e5) is independently selected from H,C₁₋₄ alkyl, and CN;

n is 0, 1, 2, or 3;

p is 0, 1, 2, 3; and

q is 0 or 1.

In some embodiments, q is 0.

In some embodiments, q is 1.

In some embodiments, ring A is phenyl.

In some embodiments, n is 0.

In some embodiments, both R⁵ and R⁶ are H.

In some embodiments, ring C is phenyl.

In some embodiments, ring C is monocyclic 5-6 membered heteroaryl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring C is phenyl, pyridyl, piperazinyl, pyrazinyl,pyrimidinyl, or pyrazolyl.

In some embodiments, ring C is phenyl, pyridyl, piperazinyl, pyrazinyl,or pyrazolyl.

In some embodiments, R⁴ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, CN, NR^(c3)R^(d3), C(O)OR^(a3), orC(O)NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)R^(d3)NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, R⁴ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, CN, or C(O)NR^(c3)R^(d3), wherein said C₁₋₆ alkyl and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, or 4 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)R^(d3)NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3), NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, R⁴ is methyl, F, Cl, CN, —C(O)OH, —C(O)NH₂,—C(O)NH(methyl), —C(O)N(CH₃)₂, —C(O)NH(2-propyl), —C(O)NH(ethyl),methoxy, 4-methylpiperazinyl, —CH₂—CN, CF₃, or a moiety of formula:

In some embodiments, R⁴ is methyl, F, Cl, CN, —C(O)NH(2-propyl),—C(O)NH(ethyl), methoxy, 4-methylpiperazinyl, —CH₂—CN, CF₃, or a moietyof formula:

In some embodiments, R⁴ is —CH₂—CN.

In some embodiments, each R³ is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, CN, OR^(a2), and C(O)NR^(c2)R^(d2), wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, each R³ is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, CN, OR^(a2), and C(O)NR^(c2)R^(d2).

In some embodiments, each R³ is independently selected from F, Cl, CF₃,and methyl.

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, p is 2.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, R^(Z) is C₁₋₄ alkyl or C₆₋₁₀ aryl-C₁₋₄ alkyl-,wherein said C₁₋₄ alkyl and C₆₋₁₀ aryl-C₁₋₄ alkyl- are each optionallysubstituted by halo, CN, or OR^(a4).

In some embodiments, R^(Z) is C₁₋₄ alkyl.

In some embodiments, R^(Z) is C₁₋₄ alkyl substituted by CN or methoxy.

In some embodiments, R^(Z) is C₆₋₁₀ aryl-C₁₋₄ alkyl- substituted byfluoro.

In some embodiments, R^(Z) is methyl, cyanomethyl, methoxymethyl, or4-fluorophenylmethyl.

In some embodiments, R^(Z) is C₁₋₄ alkyl substituted by CN.

In some embodiments, R^(Z) is cyanomethyl.

In some embodiments, R^(Z) is H.

In some embodiments, each R^(a), R^(b), R^(c), and R^(d) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁i 4 haloalkyl, C₁-4 cycanoalkyl, halo, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5) andS(O)₂NR^(c5)R^(d5).

In some embodiments, each R^(a2), R^(b2), R^(c2), and R^(d2) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁-4 cycanoalkyl, halo, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b), NR^(c5) S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5).

In some embodiments, each R^(a3), R^(b3), R^(c3), and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁i 4 haloalkyl, C₁-4 cycanoalkyl, halo, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e))NR^(c5)R^(d5),NR^(c)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5).

In some embodiments, each R^(a), R^(b), R^(c), and R^(d) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁-4alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy.

In some embodiments, each R^(a2), R^(b2), R^(c2), and R^(d2) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy.

In some embodiments, each R^(a3), R^(b3), R^(c3), and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy.

In some embodiments, each R^(a), R^(b), R^(c), and R^(d) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a2), R^(b2), R^(c2), and R^(d2) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a3), R^(b3), R^(c3), and R^(d3) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, the compound has a trans configuration with respectto the di-substituted cyclopropyl group depicted in Formula I (or any ofFormulas II, IIIa, IIIb, IVa, IVb, Va, and Vb).

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

A floating bond crossing a ring moiety in any structure or formuladepicted herein is intended to show, unless otherwise indicated, thatthe bond can connect to any ring-forming atom of the ring moiety. Forexample, where ring A in Formula I is a naphthyl group, an R¹substituent, if present, can be substituted on either of the two ringsforming the naphthyl group.

In embodiments when ring C is a fused bicyclic moiety of Formula (A),the phrase “wherein said fused bicyclic moiety of Formula (A) is bondedto ring B via ring Cl, and wherein Ring C substituents R³ and R⁴ aresubstituted on either or both of C1 and C2” is intended to denote that(1) ring B of Formula I is connected to ring C1 and not to ring C2, (2)R⁴ is substituted on either ring C1 or ring C2, and (3) any R³ that ispresent is substituted on either ring C1 or ring C2. The floating bondover ring C1 in Formula (A) is intended to show that ring C1 (not ringC2) connects to ring B.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.Throughout the definitions, the term “C_(i-j)” indicates a range whichincludes the endpoints, wherein i and j are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

The term “z-membered” (where z is an integer) typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is z. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1, 2, 3, 4-tetrahydro-naphthalene is an example ofa 10-membered cycloalkyl group.

The term “carbon” refers to one or more carbon atoms.

As used herein, the term “C_(i-j) alkyl,” employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having i to j carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_(i-j) alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has i to j carbons. Example alkoxy groupsinclude methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).In some embodiments, the alkyl group has 1 to 3 carbon atoms.

As used herein, “C_(i-j) alkenyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore double carbon-carbon bonds and having i to j carbons. In someembodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms.Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(i-j) alkynyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore triple carbon-carbon bonds and having i to j carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms.

As used herein, the term “C_(i-j) alkylamino,” employed alone or incombination with other terms, refers to a group of formula —NH(alkyl),wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylaminogroups include methylamino, ethylamino, and the like.

As used herein, the term “di-C_(i-j)-alkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂,wherein each of the two alkyl groups has, independently, i to j carbonatoms. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms. In some embodiments, the dialkylamino group is—N(C₁₋₄ alkyl)₂ such as, for example, dimethylamino or diethylamino.

As used herein, the term “C_(i-j) alkylthio,” employed alone or incombination with other terms, refers to a group of formula —S-alkyl,wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments,the alkylthio group is C₁₋₄ alkylthio such as, for example, methylthioor ethylthio.

As used herein, the term “amino,” employed alone or in combination withother terms, refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or4 fused rings) aromatic hydrocarbon, such as, but not limited to,phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and thelike. In some embodiments, aryl is C₆₋₁₀ aryl. In some embodiments, thearyl group is a naphthalene ring or phenyl ring. In some embodiments,the aryl group is phenyl.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “C_(i-j) cyanoalkyl,” employed alone or incombination with other terms, refers to an alkyl group substituted by aCN group.

As used herein, the term “C_(i-j) cycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic cyclichydrocarbon moiety having i to j ring-forming carbon atoms, which mayoptionally contain one or more alkenylene groups as part of the ringstructure.

Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or4 fused rings) ring systems. Also included in the definition ofcycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo derivatives of cyclopentane, cyclopentene, cyclohexane,and the like. One or more ring-forming carbon atoms of a cycloalkylgroup can be oxidized to form carbonyl linkages. In some embodiments,cycloalkyl is C₃₋₁₀ cycloalkyl, C₃₋₇ cycloalkyl, or C₅₋₆ cycloalkyl.Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, andthe like. Further exemplary cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, “C_(i-j) haloalkoxy,” employed alone or in combinationwith other terms, refers to a group of formula —O-haloalkyl having i toj carbon atoms. An example haloalkoxy group is OCF₃. An additionalexample haloalkoxy group is OCHF₂. In some embodiments, the haloalkoxygroup is fluorinated only. In some embodiments, the alkyl group has 1 to6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group isC₁₋₄ haloalkoxy.

As used herein, the term “halo,” employed alone or in combination withother terms, refers to a halogen atom selected from F, Cl, I or Br. Insome embodiments, “halo” refers to a halogen atom selected from F, Cl,or Br. In some embodiments, the halo substituent is F.

As used herein, the term “C_(i-j) haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has i to j carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the haloalkyl group isfluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments,the haloalkyl group is trifluoromethyl. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) aromatic heterocylic moiety, having one or moreheteroatom ring members selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ringmembers. In some embodiments, the heteroaryl group has 1, 2, or 3heteroatom ring members. In some embodiments, the heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the heteroaryl grouphas 1 heteroatom ring member. In some embodiments, the heteroaryl groupis 5- to 10-membered or 5- to 6-membered. In some embodiments, theheteroaryl group is 5-membered. In some embodiments, the heteroarylgroup is 6-membered. In some embodiments, the heteroaryl ring has orcomprises carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.When the heteroaryl group contains more than one heteroatom ring member,the heteroatoms may be the same or different. The nitrogen atoms in thering(s) of the heteroaryl group can be oxidized to form N-oxides.Example heteroaryl groups include, but are not limited to, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl,thiophenyl, triazolyl, tetrazolyl, thiadiazolyl, quinolinyl,isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1, 2-b]thiazolyl, purinyl, triazinyl, and the like.

A 5-membered heteroaryl is a heteroaryl group having five ring-formingatoms wherein one or more of the ring-forming atoms are independentlyselected from N, O, and S. In some embodiments, the 5-memberedheteroaryl group has 1, 2, or 3 heteroatom ring members. In someembodiments, the 5-membered heteroaryl group has 1 or 2 heteroatom ringmembers. In some embodiments, the 5-membered heteroaryl group has 1heteroatom ring member. Example ring-forming members include CH, N, NH,0, and S. Example five-membered ring heteroaryls are thienyl, furyl,pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2,3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2,4-oxadiazolyl, 1, 3, 4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3,4-oxadiazolyl.

A 6-membered heteroaryl is a heteroaryl group having six ring-formingatoms wherein one or more of the ring-forming atoms is N. In someembodiments, the 6-membered heteroaryl group has 1, 2, or 3 heteroatomring members. In some embodiments, the 6-membered heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the 6-memberedheteroaryl group has 1 heteroatom ring member. Example ring-formingmembers include CH and N. Example six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to non-aromatic heterocyclic ringsystem, which may optionally contain one or more unsaturations as partof the ring structure, and which has at least one heteroatom ring memberindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heterocycloalkyl group has 1, 2, 3, or 4 heteroatomring members. In some embodiments, the heterocycloalkyl group has 1, 2,or 3 heteroatom ring members. In some embodiments, the heterocycloalkylgroup has 1 or 2 heteroatom ring members. In some embodiments, theheterocycloalkyl group has 1 heteroatom ring member. In someembodiments, the heterocycloalkyl group has or comprises carbon and 1,2, or 3 heteroatoms selected from N, O, and S. When the heterocycloalkylgroup contains more than one heteroatom in the ring, the heteroatoms maybe the same or different. Example ring-forming members include CH, CH₂,C(O), N, NH, O, S, S(O), and S(O)₂. Heterocycloalkyl groups can includemono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems,including spiro systems. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the non-aromatic ring, forexample, 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran and thelike. The carbon atoms or heteroatoms in the ring(s) of theheterocycloalkyl group can be oxidized to form a carbonyl, sulfinyl, orsulfonyl group (or other oxidized linkage) or a nitrogen atom can bequaternized. In some embodiments, the heterocycloalkyl is 5- to10-membered, 4- to 10-membered, or 4- to 7-membered. Examples ofheterocycloalkyl groups include 1, 2, 3, 4-tetrahydro-quinolinyl,dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, and pyranyl.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

When the compounds of the invention contain a chiral center, thecompounds can be any of the possible stereoisomers. In compounds with asingle chiral center, the stereochemistry of the chiral center can be(R) or (S). In compounds with two chiral centers, the stereochemistry ofthe chiral centers can each be independently (R) or (S) so theconfiguration of the chiral centers can be (R) and (R), (R) and (S); (S)and (R), or (S) and (S). In compounds with three chiral centers, thestereochemistry each of the three chiral centers can each beindependently (R) or (S) so the configuration of the chiral centers canbe (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and(S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S)and (S).

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, amide—imidic acid pairs, enamine—iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified (e.g., in the case of purine rings,unless otherwise indicated, when the compound name or structure has the9H tautomer, it is understood that the 7H tautomer is also encompassed).

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in a compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (MeCN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Ed., (Mack PublishingCompany, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002).

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N, N-diisopropylethylamine); DMF (N, N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU (N, N,N′, N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography-mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MS (Mass spectrometry); Me (methyl); MeCN(acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s));mL (milliliter(s)); mmol (millimole(s)); N (normal); nM (nanomolar); NMP(N-methylpyrrolidinone); NMR (nuclear magnetic resonance spectroscopy);OTf (trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC(reverse phase high performance liquid chromatography); s (singlet); t(triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary);tt (triplet of triplets); TFA (trifluoroacetic acid); THF(tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in P. G. M. Wuts and T. W.Greene, Protective Groups in Organic Synthesis, 4^(th) Ed., Wiley &Sons, Inc., New York (2006), which is incorporated herein by referencein its entirety. Protecting groups in the synthetic schemes aretypically represented by “PG.”

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

Compounds of formula 3 can be prepared following the synthetic route asoutlined in Scheme 1. The union of cyclopropylamine derivatives offormula 1 with aldehydes of formula 2 can be accomplished throughreductive amination under standard conditions employing borohydridereducing reagents such as, but not limited to, sodiumtriacetoxyborohydride. If any functional groups in compound 1 or 2 areprotected to avoid any side reactions, a subsequent deprotection stepcan be performed to obtain the final product of formula 3. Thedeprotection conditions can be found in the literature or detailed inthe specific examples described below. The starting materials of formula1 or 2 are either commercially available, or can be prepared asdescribed herein, or prepared following methods disclosed in theliterature.

Compounds of formula 3a can be alternatively synthesized by the methodsoutlined in Scheme 2. Reductive amination of cyclopropylaminederivatives of formula 1 with aldehydes of formula 4 using similarconditions as described in Scheme 1 can give compounds of formula 5. Thefree amine group in compound 5 can then be protected with a suitableprotecting group (PG) such as but not limited to CF₃CO and Cbz, followedby selective removal of the Boc protecting group by acid to givecompound 6. Coupling of compound 6 with a (hetero)aryl-halide 7 can beachieved via direct displacement of the halide such as fluoride incompound 7 by the piperidine in compound 6 in the presence of a suitablebase (such as K₂CO₃ or NaH, etc) in a polar solvent such as DMF. Theunion of piperidine derivatives of formula 6 with (hetero)aryl-halie 7can also be achieved via palladium catalyzed amination reactions to givecompounds of formula 8, which can be deprotected to give compounds offormula 3a.

Compounds of formula 3b can be prepared by the methods outlined inScheme 3 starting from compounds of formula 1 and ketones of formula 9by reductive amination in a suitable solvent such as DCM or THF using areducing agent such as, but not limited to, sodiumtriacetoxyborohydride, optionally in the presence of an acid such asacetic acid. If any functional groups in compound 1 or 9 are protectedto avoid any side reactions, a subsequent deprotection step can beperformed to obtain the final product of formula 3b.

To synthesize cyclopropylamine derivatives of formula 1,cyclopropanation reactions can be initially carried out onα,β-unsaturated esters of formula 10 (R is, e.g., alkyl such as ethyl)under commonly applied conditions (e.g., Corey-ChaykovskyCyclopropanation, or Pd(OAc)₂ and diazomethane). The ester functionalgroup can then be converted to a primary amine via a three-stepsequence, namely saponification (e.g. LiOH in H₂O/EtOH) to elaboratecarboxylic acid 11, followed by Curtius rearrangement (e.g.(PhO)₂P(═O)N₃, Et₃N, t-BuOH), and deprotection of the amine moiety (e.g.HCl in H₂O/1,4-dioxane), to give the desired cyclopropylaminederivatives of formula 1 (See Scheme 4).

Methods of Use

Compounds of the invention are LSD1 inhibitors and, thus, are useful intreating diseases and disorders associated with activity of LSD1. Forthe uses described herein, any of the compounds of the invention,including any of the embodiments thereof, may be used.

In some embodiments, the compounds of the invention are selective forLSD1 over LSD2, meaning that the compounds bind to or inhibit LSD1 withgreater affinity or potency, compared to LSD2. In general, selectivitycan be at least about 5-fold, at least about 10-fold, at least about20-fold, at least about 50-fold, at least about 100-fold, at least about200-fold, at least about 500-fold or at least about 1000-fold.

As inhibitors of LSD1, the compounds of the invention are useful intreating LSD1-mediated diseases and disorders. The term “LSD1-mediateddisease” or “LSD1-mediated disorder” refers to any disease or conditionin which LSD1 plays a role, or where the disease or condition isassociated with expression or activity of LSD1. The compounds of theinvention can therefore be used to treat or lessen the severity ofdiseases and conditions where LSD1 is known to play a role.

Diseases and conditions treatable using the compounds of the inventioninclude generally cancers, inflammation, autoimmune diseases, viralinduced pathogenesis, beta-globinopathies, and other diseases linked toLSD1 activity.

Cancers treatable using compounds according to the present inventioninclude, for example, hematological cancers, sarcomas, lung cancers,gastrointestinal cancers, genitourinary tract cancers, liver cancers,bone cancers, nervous system cancers, gynecological cancers, and skincancers.

Example hematological cancers include, for example, lymphomas andleukemias such as acute lymphoblastic leukemia (ALL), acute myelogenousleukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-celllymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (includingrelapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), and multiple myeloma.

Example sarcomas include, for example, chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.

Example lung cancers include, for example, non-small cell lung cancer(NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated smallcell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, andmesothelioma.

Example gastrointestinal cancers include, for example, cancers of theesophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoidtumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Example genitourinary tract cancers include, for example, cancers of thekidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder andurethra (squamous cell carcinoma, transitional cell carcinoma,adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma).

Example liver cancers include, for example, hepatoma (hepatocellularcarcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma,hepatocellular adenoma, and hemangioma.

Example bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Example nervous system cancers include, for example, cancers of theskull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans),meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), aswell as neuroblastoma and Lhermitte-Duclos disease.

Example gynecological cancers include, for example, cancers of theuterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Example skin cancers include, for example, melanoma, basal cellcarcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplasticnevi, lipoma, angioma, dermatofibroma, and keloids.

The compounds of the invention can further be used to treat cancer typeswhere LSD1 may be overexpressed including, for example, breast,prostate, head and neck, laryngeal, oral, and thyroid cancers (e.g.,papillary thyroid carcinoma).

The compounds of the invention can further be used to treat geneticdisorders such as Cowden syndrome and Bannayan-Zonana syndrome.

The compounds of the invention can further be used to treat viraldiseases such as herpes simplex virus (HSV), varicella zoster virus(VZV), human cytomegalovirus, hepatitis B virus (HBV), and adenovirus.

The compounds of the invention can further be used to treatbeta-globinopathies including, for example, beta-thalassemia and sicklecell anemia.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a LSD1 protein with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having a LSD1 protein, as wellas, for example, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the LSD1protein.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

As used herein, the term “preventing” or “prevention” refers topreventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

The compounds of the invention can be used in combination treatmentswhere the compound of the invention is administered in conjunction withother treatments such as the administration of one or more additionaltherapeutic agents. The additional therapeutic agents are typicallythose which are normally used to treat the particular condition to betreated. The additional therapeutic agents can include, e.g.,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3Kinhibitors for treatment of LSD1-mediated diseases, disorders orconditions. The one or more additional pharmaceutical agents can beadministered to a patient simultaneously or sequentially.

In some embodiments, the compounds of the invention can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include the histone lysinemethyltransferases, histone arginine methyl transferases, histonedemethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases. Histone deacetylase inhibitors include, e.g.,vorinostat.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,or other anti-proliferative agents. The compounds of the invention canalso be used in combination with medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin,bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib,daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane,docetaxel, doxorubicin, dromostanolone propionate, eculizumab,epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab,panobinostat, pegaspargase, pegfilgrastim, pemetrexed disodium,pentostatin, pipobroman, plicamycin, procarbazine, quinacrine,rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib,sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone,thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine,vincristine, vinorelbine, vorinostat, and zoledronate.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with ruxolitinib.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with targeted therapies,including JAK kinase inhibitors (Ruxolitinib, JAK1-selective), Pimkinase inhibitors, PI3 kinase inhibitors including PI3K-delta selectiveand broad spectrum PI3K inhibitors, MEK inhibitors, Cyclin Dependentkinase inhibitors, b-RAF inhibitors, mTOR inhibitors, Proteasomeinhibitors (Bortezomib, Carfilzomib), HDAC-inhibitors (Panobinostat,Vorinostat), DNA methyl transferase inhibitors, dexamethasone, bromo andextra terminal family members inhibitors and indoleamine 2,3-dioxygenaseinhibitors.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with an immune suppressantsuch as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol,Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with one or more additionalagents selected from Dehydrex™ (Holles Labs), Civamide (Opko), sodiumhyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603,Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P)(Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen),15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

In some embodiments, the compound of the invention can be administeredin combination with one or more agents selected from an antibiotic,antiviral, antifungal, anesthetic, anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatories, and anti-allergicagents. Examples of suitable medicaments include aminoglycosides such asamikacin, gentamycin, tobramycin, streptomycin, netilmycin, andkanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin,ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin;naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin;paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines;rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams;cephalosporins; amphotericins; fluconazole; flucytosine; natamycin;miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen;ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline;antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided compound mayalso be combined with include: a treatment for Alzheimer's Disease suchas donepezil and rivastigmine; a treatment for Parkinson's Disease suchas L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine,pergolide, trihexyphenidyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., Avonex® andRebif®), glatiramer acetate, and mitoxantrone; a treatment for asthmasuch as albuterol and montelukast; an agent for treating schizophreniasuch as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, such as dexamethasoneor prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; an immunomodulatory agent, includingimmunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

Biological drugs, such as antibodies and cytokines, used as anticancerangents, can be combined with the compounds of the invention. Inaddition, drugs modulating microenvironment or immune responses can becombined with the compounds of the invention. Examples of such drugs areanti-Her2 antibodies, anti-CD20 antibodies, anti-CTLA1, anti-PD-1,anti-PDL1, and other immunotherapeutic drugs.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

The compounds of the invention can be provided with or used incombination with a companion diagnostic. As used herein, the term“companion diagnostic” refers to a diagnostic device useful fordetermining the safe and effective use of a therapeutic agent. Forexample, a companion diagnostic may be used to customize dosage of atherapeutic agent for a given subject, identify appropriatesubpopulations for treatment, or identify populations who should notreceive a particular treatment because of an increased risk of a seriousside effect.

In some embodiments, the companion diagnostic is used to monitortreatment response in a patient. In some embodiments, the companiondiagnostic is used to identify a subject that is likely to benefit froma given compound or therapeutic agent. In some embodiments, thecompanion diagnostic is used to identify a subject having an increasedrisk of adverse side effects from administration of a therapeutic agent,compared to a reference standard. In some embodiments, the companiondiagnostic is an in vitro diagnostic or imaging tool selected from thelist of FDA cleared or approved companion diagnostic devices. In someembodiments, the companion diagnostic is selected from the list of teststhat have been cleared or approved by the Center for Devices andRadiological Health.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating LSD1 in tissue samples,including human, and for identifying LSD1 ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes LSD1assays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2, or 3 deuterium atoms.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind LSD1 by monitoring its concentrationvariation when contacting with LSD1, through tracking of the labeling.For example, a test compound (labeled) can be evaluated for its abilityto reduce binding of another compound which is known to bind to LSD1(i.e., standard compound). Accordingly, the ability of a test compoundto compete with the standard compound for binding to LSD1 directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof LSD1 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 m particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 m particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K.

Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)].Typically, the flow rate used with 30×100 mm column was 60 mL/minute.

Example 13-Fluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile

Step 1: tert-butyl3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate

To the solution of tert-butyl 3-formylazetidine-1-carboxylate (556 mg,3.00 mmol, Alfa Aesar: Cat # H52794) and 2-phenylcyclopropanaminehydrochloride (600. mg, 3.54 mmol, trans, racemic, J&W PharmLab: Cat#20-0073 S, Lot: JW152-128A) in DCM (10 mL) was added acetic acid (510μL, 9.0 mmol). The resulting yellow solution was stirred at roomtemperature overnight then Na(OAc)₃BH (1.9 g, 9.0 mmol) was added. Thereaction mixture was stirred at room temperature for 1 h then dilutedwith DCM, washed with saturated Na₂CO₃, water and brine. The organiclayer was dried over Na₂SO₄ then concentrated. The residue was purifiedon silica gel column eluting with 0 to 100% EtOAc/Hexanes to give thedesired product (513 mg, 57%) as a light yellow oil. LC-MS calculatedfor C₁₄H₁₉N₂O₂ (M-^(t)Bu+2H)⁺: m/z=247.1; found 247.2.

Step 2: tert-butyl 3-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}azetidine-1-carboxylate

To a solution of tert-butyl3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate (187mg, 0.618 mmol) in DCM (5 mL) at 0° C. was added triethylamine (0.431mL, 3.09 mmol), followed by dropwise addition of trifluoroaceticanhydride (114 μL, 0.804 mmol). The resulting yellow solution wasstirred at 0° C. for 1 h then quenched with saturated NaHCO₃ solutionand extracted with DCM. The combined extracts were dried over Na₂SO₄then concentrated. The residue was purified on silica gel column elutingwith 0 to 60% EtOAc/Hexanes to give the desired product (228 mg, 93%) asa yellow oil. LC-MS calculated for C₁₆H₁₈F₃N₂O₃(M-^(t)Bu+2H)⁺:m/z=343.1; found 343.2.

Step 3: N-(azetidin-3-ylmethyl)-2, 2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

To the solution of tert-butyl3-{[(trans-2-phenylcyclopropyl)-(trifluoroacetyl)amino]methyl}azetidine-1-carboxylate(228 mg, 0.572 mmol) in DCM (3 mL) was added TFA (3 mL). The resultinglight yellow solution was stirred at room temperature for 1 h thenconcentrated. The residue (TFA salt) was used in the next step withoutfurther purification. LC-MS calculated for C₁₅H₁₈F₃N₂O (M+H)⁺:m/z=299.1; found 299.2.

Step 4: N-{[1-(4-cyano-2-fluorophenyl)azetidin-3-yl]methyl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

A mixture ofN-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(20 mg, 0.048 mmol), 3,4-difluorobenzonitrile (6.7 mg, 0.048 mmol) andpotassium carbonate (16 mg, 0.12 mmol) in DMF (0.5 mL) was stirred at120° C. for 2 h. The reaction mixture was then cooled to roomtemperature, diluted with EtOAc, filtered and concentrated under reducedpressure to afford the crude product which was used in the next stepwithout further purification. LC-MS calculated for C₂₂H₂₀F₄N₃O (M+H)⁺:m/z=418.2; found 418.1.

Step 5:.3-Fluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile

The crude product from Step 4 was dissolved in THF (0.5 mL) and MeOH(0.5 mL) then 1 N sodium hydroxide in water (0.5 mL) was added. Thereaction mixture was stirred at 40° C. for 1 h then cooled to roomtemperature, filtered and purified by prep. HPLC (pH=10,acetonitrile/water+NH₄OH) to afford the desired product. LC-MScalculated for C₂₀H₂₁FN₃ (M+H)⁺: m/z=322.2; found 322.1.

Example 23,5-Difluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 1 with 3,4,5-trifluorobenzonitrilereplacing 3,4-difluorobenzonitrile in Step 4. LC-MS calculated forC₂₀H₂₀F₂N₃ (M+H)⁺: m/z=340.2; found 340.1.

Example 32,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 1 with 2,4,5-trifluoro-N-isopropylbenzamide(prepared using similar methods as disclosed in the literature such asWO 2012/177606) replacing 3,4-difluorobenzonitrile in Step 4. LC-MScalculated for C₂₃H₂₈F₂N₃O (M+H)⁺: m/z=400.2; found 400.2.

Example 42-Methyl-6-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]nicotinonitrile

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 1 with 6-fluoro-2-methylnicotinonitrilereplacing 3,4-difluorobenzonitrile in Step 4. LC-MS calculated forC₂₀H₂₃N₄ (M+H)⁺: m/z=319.2; found 319.1.

Example 5N-Ethyl-5-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)pyrazine-2-carboxamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 1 with5-chloro-N-ethylpyrazine-2-carboxamide (prepared using similar methodsas disclosed in the literature such as WO 2012/177606) replacing3,4-difluorobenzonitrile in Step 4. LC-MS calculated for C₂₀H₂₆N₅O(M+H)⁺: m/z=352.2; found 352.2.

Example 63,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 1 with 3,4,5-trifluoro-N-isopropylbenzamide(prepared using similar methods as disclosed in the literature such asWO 2012/177606) replacing 3,4-difluorobenzonitrile in Step 4. LC-MScalculated for C₂₃H₂₈F₂N₃O (M+H)⁺: m/z=400.2; found 400.2.

Example 72,6-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 1 with 2,4,6-trifluoro-N-isopropylbenzamide(prepared using similar methods as disclosed in the literature such asWO 2012/177606) replacing 3,4-difluorobenzonitrile in Step 4. LC-MScalculated for C₂₃H₂₈F₂N₃O (M+H)⁺: m/z=400.2; found 400.2.

Example 82,3-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

A container with a mixture ofN-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(23 mg, 0.056 mmol, prepared as described in Example 1, Step 3),4-bromo-2,3-difluoro-N-isopropylbenzamide (24 mg, 0.084 mmol, preparedusing similar methods as disclosed in the literature such as WO2012/177606), palladium acetate (1 mg, 0.006 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4 mg, 0.006 mmol),and cesium carbonate (55 mg, 0.17 mmol) in 1,4-dioxane (1 mL) wasevacuated then refilled with nitrogen. After stirring at 125° C.overnight, the reaction mixture was cooled to room temperature, then 1NNaOH (0.5 mL) and MeOH (1 mL) were added. The resulting mixture wasstirred at 40° C. for 1 h then cooled to room temperature, filtered andpurified by prep HPLC (pH=10, acetonitrile/water+NH₄OH) to afford thedesired product. LC-MS calculated for C₂₃H₂₈F₂N₃O (M+H)⁺: m/z=400.2;found 400.1.

Example 92-Chloro-5-fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 8 with4-bromo-2-chloro-5-fluoro-N-isopropylbenzamide (prepared using similarmethods as disclosed in the literature such as WO 2012/177606) replacing4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated forC₂₃H₂₈ClFN₃O (M+H)⁺: m/z=416.2; found 416.1.

Example 103-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 8 with4-bromo-3-fluoro-N-isopropylbenzamide (prepared using similar methods asdisclosed in the literature such as WO 2012/177606) replacing4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated forC₂₃H₂₉FN₃O (M+H)⁺: m/z=382.2; found 382.2.

Example 112-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 8 with4-bromo-2-fluoro-N-isopropylbenzamide (prepared using similar methods asdisclosed in the literature such as WO 2012/177606) replacing4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated forC₂₃H₂₉FN₃O (M+H): m/z=382.2; found 382.2.

Example 122-Fluoro-N-isopropyl-5-methyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 8 with4-bromo-2-fluoro-N-isopropyl-5-methylbenzamide (prepared using similarmethods as disclosed in the literature such as WO 2012/177606) replacing4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated forC₂₄H₃₁FN₃O (M+H)⁺: m/z=396.2; found 396.4.

Example 13N-Isopropyl-2-methoxy-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 8 with4-bromo-N-isopropyl-2-methoxybenzamide (prepared using similar methodsas disclosed in the literature such as WO 2012/177606) replacing4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated forC₂₄H₃₂N₃O₂ (M+H)⁺: m/z=394.2; found 394.4.

Example 143-Chloro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 8 with4-bromo-3-chloro-N-isopropylbenzamide (prepared using similar methods asdisclosed in the literature such as WO 2012/177606) replacing4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculated forC₂₃H₂₉C1N₃O (M+H)⁺: m/z=398.2; found 398.2.

Example 155-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 8 with5-bromo-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide(prepared using similar methods as disclosed in the literature such asWO 2012/177606) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide.LC-MS calculated for C₂₃H₂₆F₃N₄O (M+H)⁺: m/z=431.2; found 431.2.

Example 16N-({1-[6-(4-Methylpiperazin-1-yl)pyrimidin-4-yl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 8 with4-chloro-6-(4-methylpiperazin-1-yl)pyrimidine (Combi-Blocks, cat #QA-3632) replacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MScalculated for C₂₂H₃₁N₆(M+H)⁺: m/z=379.3; found 379.4.

Example 17trans-N-{[1-(1-Methyl-1H-pyrazol-4-yl)azetidin-3-yl]methyl}-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 8 with 4-bromo-1-methyl-1H-pyrazolereplacing 4-bromo-2,3-difluoro-N-isopropylbenzamide. LC-MS calculatedfor C₁₇H₂₃N₄(M+H)⁺: m/z=283.2; found 283.2.

Example 182-Chloro-6-(4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)benzonitrile

Step 1: 1-tert-butyl 4-methyl4-(cyanomethyl)piperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate(0.97 g, 4.0 mmol) in THF (20 mL) at −40° C. was added 2.0 M LDA in THF(2.8 mL, 5.6 mmol) dropwise. The resulting mixture was stirred at −40°C. for 30 min then bromoacetonitrile (0.44 mL, 6.4 mmol) was added. Thereaction mixture was stirred at −40° C. for 2 h then quenched withwater. The mixture was warmed to room temperature then diluted withEtOAc, washed with water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with EtOAc in hexane(0-30%) to give the desired product. LC-MS calculated for C₁₀H₁₅N₂O₄(M-^(t)Bu+2H)⁺: m/z=227.1; found 227.2.

Step 2:. 1-(tert-Butoxycarbonyl)-4-(cyanomethyl)piperidine-4-carboxylicAcid

To the solution of 1-tert-butyl 4-methyl4-(cyanomethyl)piperidine-1,4-dicarboxylate (0.60 g, 2.1 mmol) in THF(4.0 mL)/MeOH (4.0 mL)/water (1.0 mL) was added lithium hydroxide(monohydrate, 0.44 g, 11 mmol). The reaction mixture was stirred at roomtemperature for 2 h then acidified with cold 1 N HCl and extracted withEtOAc. The extract was washed with water, brine, dried over Na₂SO₄,filtered and concentrated. The residue was used in the next step withoutfurther purification. LC-MS calculated for C₉H₁₃N₂O₄ (M-^(t)Bu+2H)⁺:m/z=213.1; found 213.1.

Step 3: tert-Butyl4-(cyanomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of1-(tert-butoxycarbonyl)-4-(cyanomethyl)piperidine-4-carboxylic acid(0.50 g, 1.9 mmol) and triethylamine (0.52 mL, 3.7 mmol) in THF (6 mL)at 0° C. was added ethyl chloroformate (0.21 mL, 2.2 mmol). Theresulting mixture was stirred for 30 min then filtered and washed withTHF (2 mL). The filtrate was cooled to 0° C. and then sodiumtetrahydroborate (0.14 g, 3.7 mmol) in methanol (1 mL)/water (1 mL) wasadded. The mixture was warmed to room temperature then stirred for 30min. The mixture was diluted with EtOAc, washed with saturated NaHCO₃,water and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was used in the next step without furtherpurification. LC-MS calculated for C₉H₁₅N₂O₃ (M-^(t)Bu+2H)⁺: m/z=199.1;found 199.1.

Step 4: tert-Butyl 4-(cyanomethyl)-4-formylpiperidine-1-carboxylate

To a solution of tert-butyl4-(cyanomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (400.0 mg,1.573 mmol) in DCM (8 mL) was added Dess-Martin periodinane (1.0 g, 2.4mmol). The resulting mixture was stirred at room temperature for 3 hthen saturated Na₂S₂O₃ aqueous solution was added and stirred for 10min. The mixture was diluted with DCM, washed with 1N NaOH, water andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on asilica gel column eluting with EtOAc in hexane (0-30%) to give thedesired product. LC-MS calculated for C₉H₁₃N₂O₃ (M-^(t)Bu+2H)⁺:m/z=197.1; found 197.1.

Step 5: tert-Butyl4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate

To the solution of tert-butyl4-(cyanomethyl)-4-formylpiperidine-1-carboxylate (180.0 mg, 0.7134 mmol)and 2-phenylcyclopropanamine (114 mg, 0.856 mmol, trans, racemic, J&WPharmLab: Cat #20-0073S) in DCM (3.0 mL) was added acetic acid (0.061mL, 1.1 mmol). The mixture was stirred at r.t. for 2 h then sodiumtriacetoxyborohydride (300 mg, 1.4 mmol) was added. The resultingmixture was stirred at r.t. for 2 h then diluted with DCM, washed withsaturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with methanol in methylenechloride (0-8%) to give the desired product. LC-MS calculated forC₂₂H₃₂N₃O₂ (M+H)⁺: m/z=370.2; found 370.3.

Step 6: tert-Butyl 4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

To a solution of tert-butyl4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate(0.18 g, 0.49 mmol) and DIEA (0.17 mL, 0.97 mmol) in DCM (2.4 mL) at 0°C. was added dropwise trifluoroacetic anhydride (0.08 mL, 0.58 mmol).The mixture was warmed to room temperature and stirred for 1 h thendiluted with DCM, washed with saturated NaHCO₃, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with EtOAc in hexane (0-20%) to give the desired product. LC-MScalculated for C₂₀H₂₃F₃N₃O₃(M-^(t)Bu+2H)⁺: m/z=410.2; found 410.1.

Step 7:N-{[4-(Cyanomethyl)piperidin-4-yl]methyl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

To a solution of tert-butyl4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate(0.16 g, 0.34 mmol) in DCM (0.2 mL) was added 4.0 M hydrogen chloride indioxane (0.8 mL, 3.2 mmol). The resulting mixture was stirred at roomtemperature for 30 min then concentrated. The residue was used in thenext step without further purification. LC-MS calculated for C₁₉H₂₃F₃N₃O(M+H)⁺: m/z=366.2; found 366.1.

Step 8:2-Chloro-6-(4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)benzonitrile

To a solution ofN-{[4-(cyanomethyl)piperidin-4-yl]methyl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(15.0 mg, 0.0410 mmol) and 2-chloro-6-fluorobenzonitrile (13 mg, 0.082mmol) in NMP (0.4 mL) was added DIEA (29 μL, 0.16 mmol). The resultingmixture was stirred at 140° C. for 3 h then cooled to room temperatureand 1 N NaOH (1.0 mL) was added. The mixture was stirred at 40° C. for 2h then cooled to room temperature and purified by prep HPLC (pH=2,acetonitrile/water+TFA) to afford the desired product as TFA salt. LC-MScalculated for C₂₄H₂₆C1N₄ (M+H)⁺: m/z=405.2; found 405.1.

Example 19{4-{[(trans-2-Phenylcyclopropyl)amino]methyl}-1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}acetonitrile

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 18 with2-chloro-3-(trifluoromethyl)pyridine replacing2-chloro-6-fluorobenzonitrile. LC-MS calculated for C₂₃H₂₆F₃N₄ (M+H):m/z=415.2; found 415.3.

Example 206-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

Step 1: 1-tert-butyl 4-methyl4-(4-fluorobenzyl)piperidine-1,4-dicarboxylate

To a solution of N,N-diisopropylamine (4.9 mL, 35 mmol) intetrahydrofuran (80 mL) at −78° C. was added n-butyllithium (2.5 M inhexanes, 14 mL, 35 mmol). The resulting mixture was warmed to −20° C.and stirred for 10 min then cooled to −78° C. and a solution of1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (AstaTech, cat #B56857: 6.08 g, 25.0 mmol) in THF (10 mL) was slowly added. The reactionmixture was slowly warmed to −40° C. and stirred for 1 h. The mixturewas then cooled to −78° C. and α-bromo-4-fluorotoluene (4.9 mL, 40.mmol) was added. The reaction mixture was stirred at −78° C. for 1 hthen quenched with saturated NH₄Cl, warmed to room temperature anddiluted with ethyl ether. The mixture was then washed with water, brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with EtOAc inhexane (0-20%) to give the desired product (6.5 g, 74%). LC-MScalculated for C₁₅H₁₉FNO₄ (M-^(t)Bu+2H)⁺: m/z=296.1; found 296.1.

Step 2: tert-butyl4-(4-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl4-(4-fluorobenzyl)piperidine-1,4-dicarboxylate (6.5 g, 18 mmol) intetrahydrofuran (90 mL) at 0° C. was added LiAlH₄ (1 M in THF, 24 mL, 24mmol) slowly. The resulting mixture was stirred at 0° C. for 30 min thenwater (0.9 mL) was added, followed by NaOH (15 wt % in water, 0.9 mL)and water (0.9 mL). The mixture was stirred for 20 min then filtered andwashed with THF. The filtrate was concentrated and the residue (5.8 g,97%) was used in the next step without further purification. LC-MScalculated for C₁₄H₁₉FNO₃ (M-^(t)Bu+2H)⁺: m/z=268.1; found 268.1.

Step 3: tert-butyl 4-(4-fluorobenzyl)-4-formylpiperidine-1-carboxylate

A solution of dimethyl sulfoxide (4.3 mL, 60. mmol) in methylenechloride (6 mL) was added to a solution of oxalyl chloride (2.6 mL, 30mmol) in methylene chloride at −78° C. over 10 min and then theresulting mixture was warmed to −60° C. over 25 min. A solution oftert-butyl 4-(4-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate(5.2 g, 16 mmol) in methylene chloride (6 mL) was slowly added and thenwarmed to −45° C. over 30 mins. N,N-Diisopropylethylamine (21 mL, 120mmol) was then added and the mixture was warmed to 0° C. over 15 min.The mixture was poured into a cold 1 N HCl aqueous solution and thenextracted with ethyl ether. The combined extracts were dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with EtOAc in hexane(0-20%) to give the desired product (4.3 g, 83%). LC-MS calculated forC₁₄H₁₇FNO₃ (M-^(t)Bu+2H)⁺: m/z=266.1; found 266.1.

Step 4:. tert-butyl4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-fluorobenzyl)-4-formylpiperidine-1-carboxylate (4.2 g, 13 mmol) and(1R, 2S)-2-phenylcyclopropanamine (1.96 g, 14.7 mmol) (prepared usingprocedures as described in Bioorg. Med. Chem. Lett., 2011, 21, 4429) in1,2-dichloroethane (50 mL) was added acetic acid (1.1 mL, 20. mmol). Theresulting mixture was stirred at room temperature for 2 h then sodiumtriacetoxyborohydride (5.7 g, 27 mmol) was added. The reaction mixturewas stirred at room temperature for 5 h then diluted with methylenechloride, washed with 1 N NaOH aqueous solution, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with MeOH in DCM (0-6%) to give the desired product (5.0 g,87%). LC-MS calculated for C₂₇H₃₆FN₂O₂(M+H)⁺: m/z=439.3; found 439.2.

Step 5: tert-butyl 4-(4-fluorobenzyl)-4-{[(JR,2S)-2-phenylcyclopropyl-(trifluoroacetyl)amino]-methyl}piperidine-1-carboxylate

Trifluoroacetic anhydride (2.08 mL, 14.7 mmol) was added to a solutionof tert-butyl4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate(4.3 g, 9.8 mmol) and N,N-diisopropylethylamine (4.3 mL, 24 mmol) inmethylene chloride (40 mL) at 0° C. The resulting mixture was stirred at0° C. for 1 h then diluted with ether and washed with 1 N HCl, water andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on asilica gel column eluting with EtOAc in hexanes (0-30%) to give thedesired product (4.6 g, 88%). LC-MS calculated for C₂₅H₂₇F₄N₂O₃(M-^(t)Bu+2H)⁺: m/z=479.2; found 479.2.

Step 6:2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

Hydrogen chloride (4 M in 1,4-dioxane, 20 mL, 80 mmol) was added to asolution of tert-butyl4-(4-fluorobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}-piperidine-1-carboxylate(4.6 g, 8.6 mmol) in methylene chloride (6 mL). The resulting mixturewas stirred at room temperature for 30 min then concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₂₄H₂₇F₄N₂O (M+H)⁺: m/z=435.2; found 435.2.

Step 7:6-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

N,N-Diisopropylethylamine (0.040 mL, 0.23 mmol) was added to a mixtureof2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(25.0 mg, 0.0575 mmol) and methyl 6-fluoropyridine-2-carboxylate(Aldirch, cat #697842: 0.018 g, 0.12 mmol) in dimethyl sulfoxide (0.3mL). The resulting mixture was stirred at 140° C. for 1.5 h then cooledto room temperature and NaOH (15 wt % in water, 0.5 mL) was added. Themixture was stirred at room temperature for 2 h then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₈H₃₁FN₃O₂(M+H)⁺: m/z=460.2; found460.2.

Example 215-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

This compound was prepared using similar procedures as described forExample 20 with methyl 5-fluoropyridine-2-carboxylate (Combi-Blocks, cat# PY-1211) replacing methyl 6-fluoropyridine-2-carboxylate. The mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₈H₃₁FN₃O₂(M+H)⁺:m/z=460.2; found 460.2.

Example 221-{4-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]phenyl}cyclopropanecarboxylicAcid

To a mixture of2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 20, Step 6: 25 mg, 0.058 mmol), palladium acetate (0.6 mg,0.003 mmol), (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (35 mg,0.056 mmol), and cesium carbonate (56 mg, 0.17 mmol) in 1,4-dioxane(0.29 mL, 3.8 mmol) was added methyl1-(4-bromophenyl)cyclopropanecarboxylate (Combi-Blocks, cat # HC-3048:22 mg, 0.086 mmol). The resulting mixture was purged with nitrogen thenstirred at 130° C. for overnight. The mixture was cooled to roomtemperature, diluted with acetonitrile and then filtered. The filtratewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired intermediate. The intermediate was dissolved in MeOH/THF(0.2/0.2 mL) and then NaOH (15 wt % in water, 1.0 mL) was added. Theresulting mixture was stirred at room temperature for 6 h then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₃₂H₃₆FN₂O₂(M+H)⁺: m/z=499.3;found 499.2.

Example 234-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

Step 1: 1-tert-butyl 4-methyl4-(methoxymethyl)piperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate(AstaTech, cat # B56857: 2.43 g, 10.0 mmol) in tetrahydrofuran (30 mL)at −40° C. was added lithium diisopropylamide (2 M in THF, 5.8 mL, 12mmol). The resulting mixture was stirred at −40° C. for 30 min thenchloromethyl methyl ether (1.2 mL, 16 mmol) was added. The reactionmixture was stirred at −40° C. for 1 h then quenched with saturatedNH₄Cl aqueous solution and warmed to room temperature. The mixture wasdiluted with ethyl acetate, washed with saturated NaHCO₃ aqueoussolution, water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The crude material was purified via flashchromatography on a silica gel column (0 to 20% EtOAc in hexanes) togive the desired product (2.6 g, 90%). LC-MS calculated for C₉H₁₈NO₃(M-Boc+2H)⁺: m/z=188.1; found 188.1.

Step 2: tert-butyl4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl4-(methoxymethyl)piperidine-1,4-dicarboxylate (2.3 g, 8.0 mmol) intetrahydrofuran (40 mL) at 0° C. was added LiAlH₄ (1 M in THF, 10. mL,10. mmol) slowly. The resulting mixture was stirred at 0° C. for 30 minthen quenched with addition of water (0.1 mL), NaOH (15 wt % in water,0.1 mL) and water (0.1 mL). The mixture was stirred for 10 min thenfiltered and washed with THF. The filtrate was concentrated and theresidue was used in the next step without further purification. LC-MScalculated for C₉H₁₈NO₄ (M-^(t)Bu+2H)⁺: m/z=204.1; found 204.1.

Step 3: tert-butyl 4-formyl-4-(methoxymethyl)piperidine-1-carboxylate

Dimethyl sulfoxide (1.7 mL, 24 mmol) in methylene chloride (2 mL) wasadded to a solution of oxalyl chloride (1.0 mL, 12 mmol) in methylenechloride (3 mL) at −78° C. over 10 min. The resulting mixture was warmedto −60 OC over 25 min then a solution of tert-butyl4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate (1.6 g, 6.0mmol) in methylene chloride (5 mL) was slowly added. The mixture waswarmed to −45° C. over 30 min then triethylamine (6.7 mL, 48 mmol) wasadded. The mixture was warmed to 0° C. over 15 min. The reaction mixturewas then poured into a cold 1 N HCl aqueous solution and extracted withdiethyl ether. The combined extracts were dried over Na₂SO₄, filteredand concentrated. The residue was purified via flash chromatography on asilica gel column eluting with 0 to 20% EtOAc in hexanes to give thedesired product (1.3 g, 84%). LC-MS calculated for C₈H₁₆NO₂ (M-Boc+2H)⁺:m/z=158.1; found 158.1.

Step 4: tert-butyl4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

A mixture of tert-butyl4-formyl-4-(methoxymethyl)piperidine-1-carboxylate (1.3 g, 5.0 mmol),acetic acid (0.43 mL, 7.5 mmol) and (1R,2S)-2-phenylcyclopropanamine(699 mg, 5.25 mmol) in 1,2-dichloroethane (20 mL) was stirred at roomtemperature for 1 h then sodium triacetoxyborohydride (2.1 g, 10. mmol)was added. The resulting mixture was stirred at room temperature for 2 hthen diluted with methylene chloride, washed with saturated NaHCO₃aqueous solution, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified via flashchromatography on a silica gel column eluting with 0 to 8% methanol inDCM to give the desired product (1.7 g, 91%). LC-MS calculated forC₂₂H₃₅N₂O₃ (M+H)⁺: m/z=375.3; found 375.2.

Step 5: tert-butyl4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl]-(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution oftert-butyl4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate(1.7 g, 4.5 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.1 mmol) inmethylene chloride (25 mL) at 0° C. The resulting mixture was stirred atroom temperature for 1 h then diluted with methylene chloride, washedwith sat. NaHCO₃ aqueous solution, water, and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified via flash chromatography on a silica gel column eluting with 0to 20% EtOAc in hexanes to give the desired product (1.8 g, 84%). LC-MScalculated for C₁₉H₂₆F₃N₂O₂(M-Boc+2H)⁺: m/z=371.2; found 371.1.

Step 6:2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

4.0 M Hydrogen chloride in dioxane (7 mL, 28 mmol) was added to asolution of tert-butyl4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl})-piperidine-1-carboxylate(1.8 g, 3.8 mmol) in methylene chloride (4 mL). The resulting mixturewas stirred at room temperature for 30 min then concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₁₉H₂₆F₃N₂O₂(M+H)⁺: m/z=371.2; found 371.2.

Step 7:4-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

To a solution of2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(90. mg, 0.24 mmol) and methyl 4-fluoropyridine-2-carboxylate (0.075 g,0.48 mmol) in dimethyl sulfoxide (0.5 mL) was addedN,N-diisopropylethylamine (0.17 mL, 0.97 mmol). The resulting mixturewas stirred at 140° C. for 1.5 h then cooled to room temperature andNaOH (15 wt % in water, 0.5 mL) was added. The reaction mixture wasstirred at room temperature for 5 h then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₃H₃₀N₃O₃ (M+H)⁺: m/z=396.2; found 396.2.

Example 246-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

This compound was prepared using procedures analogous to those describedfor Example 23 with methyl 6-fluoropyridine-2-carboxylate replacingmethyl 4-fluoropyridine-2-carboxylate. The reaction mixture was purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₂₃H₃₀N₃O₃ (M+H)⁺: m/z=396.2;found 396.2.

Example 255-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

Step 1: tert-butyl4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate(Synnovator, cat # PBN2011767: 2.50 g, 11.0 mmol), acetic acid (0.94 mL,16 mmol) and (1R,2S)-2-phenylcyclopropanamine (1.54 g, 11.5 mmol) in1,2-dichloroethane (40 mL) was stirred at room temperature for 1 h thensodium triacetoxyborohydride (4.7 g, 22 mmol) was added. The mixture wasstirred at room temperature for 2 h then diluted with methylenechloride, washed with saturated NaHCO₃, water and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified via flash chromatography on a silica gel column eluting with 0to 8% MeOH in DCM to give the desired product (3.4 g, 90%). LC-MScalculated for C₂₁H₃₃N₂O₂ (M+H): m/z=345.3; found 345.2.

Step 2:. tert-butyl4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}-piperidine-1-carboxylate

Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution oftert-butyl4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate(1.6 g, 4.5 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.1 mmol) inmethylene chloride (25 mL) at 0° C. The resulting mixture was stirred atroom temperature for 1 h then diluted with methylene chloride, washedwith saturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified via flashchromatography on a silica gel column eluting with 0 to 20% EtOAc inhexanes to give the desired product (1.8 g, 90%). LC-MS calculated forC₁₉H₂₄F3N₂O₃(M-^(t)Bu+2H)⁺: m/z=385.2; found 385.2.

Step 3:2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]-acetamide

To a solution of tert-butyl4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)-amino]methyl}piperidine-1-carboxylate(1.5 g, 3.4 mmol) in methylene chloride (3 mL) was added hydrogenchloride (4 M in 1,4-dioxane, 6 mL, 24 mmol). The resulting mixture wasstirred at room temperature for 1 h then concentrated. The residue wasused in the next step without further purification. LC-MS calculated forC₁₈H₂₄F₃N₂O (M+H)⁺: m/z=341.2; found 341.2.

Step 4:5-[4-methyl-4-({[(R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

N,N-Diisopropylethylamine (61 μL, 0.35 mmol) was added to a solution of2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(30. mg, 0.088 mmol) and methyl 5-fluoropyridine-2-carboxylate (27 mg,0.18 mmol) in N-methylpyrrolidinone (0.5 mL). The resulting mixture wasstirred at 130° C. for overnight then cooled to room temperature andconcentrated. The residue was dissolved in THF (1.0 mL) then 1 N NaOH(1.0 mL) was added. The mixture was stirred at room temperature for 5 hthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₂H₂₈N₃O₂ (M+H)⁺:m/z=366.2; found 366.2. ¹H NMR (500 MHz, DMSO) δ 8.35 (d, J=2.9 Hz, 1H),7.88 (d, J=8.9 Hz, 1H), 7.41 (dd, J=9.0, 2.9 Hz, 1H), 7.35-7.26 (m, 2H),7.26-7.12 (m, 3H), 3.70-3.53 (m, 2H), 3.36-3.21 (m, 2H), 3.18-3.08 (m,2H), 3.06-2.93 (m, 1H), 2.57-2.50 (m, 1H), 1.68-1.57 (m, 2H), 1.57-1.44(m, 3H), 1.34-1.24 (m, 1H), 1.11 (s, 3H).

Example 266-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

N,N-Diisopropylethylamine (0.15 mL, 0.86 mmol) was added to a mixture of2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 25, Step 3: 74 mg, 0.22 mmol) and methyl6-fluoropyridine-2-carboxylate (67 mg, 0.43 mmol) in dimethyl sulfoxide(0.5 mL). The resulting mixture was stirred at 140° C. for 1.5 h thencooled to room temperature and NaOH (15 wt % in water, 0.5 mL) wasadded. The reaction mixture was stirred at room temperature for 5 h thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₂H₂₈N₃O₂ (M+H)⁺:m/z=366.2; found 366.2. ¹H NMR (500 MHz, DMSO) δ 8.58 (br, 2H), 7.65(dd, J=8.6, 7.3 Hz, 1H), 7.35-7.24 (m, 3H), 7.25-7.14 (m, 3H), 7.07 (d,J=8.5 Hz, 1H), 4.00-3.81 (m, 2H), 3.43-3.29 (m, 2H), 3.16-3.07 (m, 2H),3.07-2.97 (m, 1H), 2.56-2.49 (m, 1H), 1.63-1.49 (m, 3H), 1.48-1.37 (m,2H), 1.35-1.22 (m, 1H), 1.11 (s, 3H).

Example 274-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicAcid

This compound was prepared using procedures analogous to those describedfor Example 26. The mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₂₈N₃O₂ (M+H)⁺: m/z=366.2; found 366.2.

Example 28N,N-dimethyl-5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxamide

To a solution of5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylicacid (Example 25: 9.2 mg, 0.025 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(21.0 mg, 0.0403 mmol) in N,N-dimethylformamide (0.6 mL) was addeddimethylamine (2 M in THF, 0.2 mL, 0.5 mmol), followed by triethylamine(24 μL, 0.17 mmol). The resulting mixture was stirred at roomtemperature for 1 h then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₃₃N₄O (M+H)⁺: m/z=393.3; found 393.3. ¹H NMR(500 MHz, DMSO) δ 8.60 (br, 2H), 8.26 (d, J=2.8 Hz, 1H), 7.49 (d, J=8.8Hz, 1H), 7.40 (dd, J=8.8, 2.9 Hz, 1H), 7.35-7.26 (m, 2H), 7.26-7.15 (m,3H), 3.57-3.47 (m, 2H), 3.25-3.16 (m, 2H), 3.15-3.09 (m, 2H), 3.08-2.91(m, 7H), 2.54-2.50 (m, 1H), 1.68-1.58 (m, 2H), 1.57-1.45 (m, 3H),1.34-1.25 (m, 1H), 1.10 (s, 3H).

Example 29N-methyl-5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxamide

This compound was prepared using procedures analogous to those describedfor Example 28. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₃H₃₁N₄O (M+H)⁺: m/z=379.2; found 379.2.

Example 302-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)pyrimidin-4-amine

Step 1: 1-(4-aminopyrimidin-2-yl)piperidin-4-one

To the mixture of 2-chloropyrimidin-4-amine (130 mg, 1.00 mmol) andpiperidin-4-one hydrochloride hydrate (169 mg, 1.10 mmol) in isopropylalcohol (5 mL) was added N,N-diisopropylethylamine (435 μL, 2.50 mmol).The resulting suspension was heated to 100° C. and stirred forovernight. The reaction mixture was cooled to room temperature thendiluted with EtOAc and washed with water and brine. The organic layerwas dried over Na₂SO₄ then concentrated to give the desired product as ayellow solid, which was used in the next step without furtherpurification. LC-MS calculated for C₉H₁₃N₄O (M+H)⁺: m/z=193.1; found193.2.

Step 2:2-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)pyrimidin-4-amine

To the solution of (1R,2S)-2-phenylcyclopropanamine (24. mg, 0.18 mmol)and 1-(4-aminopyrimidin-2-yl)piperidin-4-one (34 mg, 0.18 mmol) inmethylene chloride (1 mL) was added acetic acid (30 μL, 0.53 mmol). Theresulting mixture was stirred at room temperature for overnight thensodium triacetoxyborohydride (75 mg, 0.35 mmol) was added. The reactionmixture was stirred at room temperature for 2 h then diluted with DCMand washed with saturated NaHCO₃ aqueous solution, water and brine. Theorganic layer was dried over Na₂SO₄ then concentrated. The residue wasdissolved in acetonitrile then purified by prep HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desire product as a white solid.LC-MS calculated for C₁₈H₂₄N₅(M+H)⁺: m/z=310.2; found 310.1.

Example 31 2-(4-{[(1S,2R)-2-phenylcyclopropyl]amino}piperidin-1-yl)pyrimidin-4-amine

This compound was prepared using procedures analogous to those describedfor Example 30 with (1S,2R)-2-phenylcyclopropanamine (prepared usingprocedures as described in Bioorg. Med. Chem. Lett., 2011, 21, 4429)replacing (1R,2S)-2-phenylcyclopropanamine. The reaction mixture waspurified by prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give thedesired product as a white solid. LC-MS calculated for C₁₈H₂₄N₅(M+H)⁺:m/z=310.2; found 310.1.

Example A: LSD1 Histone Demethylase Biochemical Assay

LANCE LSD1/KDM1A demethylase assay-10 μL of 1 nM LSD-1 enzyme (ENZOBML-SE544-0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20,25 mM NaCl, 5 mM DTT) were preincubated for 1 hour at 25° C. with 0.8 μLcompound/DMSO dotted in black 384 well polystyrene plates. Reactionswere started by addition of 10 μL of assay buffer containing 0.4 μMBiotin-labeled Histone H3 peptide substrate:ART-K(Me1)-QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO: 1 (AnaSpec 64355)and incubated for 1 hour at 25° C. Reactions were stopped by addition of10 μL 1× LANCE Detection Buffer (PerkinElmer CR97-100) supplemented with1.5 nM Eu-anti-unmodified H3K4 Antibody (PerkinElmer TRF0404), and 225nM LANCE Ultra Streptavidin (PerkinElmer TRF 102) along with 0.9 mMTranylcypromine-HCl (Millipore 616431). After stopping the reactionsplates were incubated for 30 minutes and read on a PHERAstar FS platereader (BMG Labtech). Compounds having an IC₅₀ of 1 μM or less wereconsidered active. IC₅₀ data for the example compounds is provided inTable 1 (+ refers to IC₅₀≤100 nM; ++ refers to IC₅₀>100 nM and ≤500 nM).

TABLE 1 Example No. IC₅₀ (nM) 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 +11 + 12 + 13 + 14 + 15 + 16 + 17 + 18 + 19 + 20 + 21 + 22 + 23 + 24 +25 + 26 + 27 + 28 + 29 + 30 + 31 ++

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: X is —CH₂—; Y is—CH₂— or —CH₂—CH₂—; wherein each R² is substituted on any ring-formingcarbon atom of the ring in Formula II containing X and Y except thering-forming carbon atom to which R^(Z) is bonded; ring A is phenyl;ring C is (1) phenyl, (2) monocyclic 5-6 membered heteroaryl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (3) afused bicyclic moiety having Formula (A):

wherein: ring C1 is phenyl or 5-6 membered heteroaryl having carbon and1, 2, 3 or 4 heteroatoms selected from N, O, and S; ring C2 is (1)phenyl, (2) C₅₋₆ cycloalkyl, (3) 5-6 membered heteroaryl having carbonand 1, 2, 3 or 4 heteroatoms selected from N, O, and S, or (4) 5-6membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatomsselected from N, O, and S; wherein said fused bicyclic moiety of FormulaA is bonded to ring B via ring Cl, and wherein Ring C substituents R³and R⁴ are substituted on either or both of C1 and C2; wherein ring C issubstituted on any ring-forming atom of ring

except the ring-forming atom of ring

to which R^(Z) is bonded; each R¹ is independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d)d, NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); each R² isindependently selected from halo, C₁₋₆ alkyl, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), NRclR^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein each R² is substituted on anyring-forming atom of ring B except the ring-forming atom of ring B towhich R^(Z) is bonded; each R³ is independently selected from halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a2), SR, C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)C(═NR^(e2))NR^(c2)R^(d2)NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2) NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2)NR^(c2)C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); R⁴ is halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3)OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3)NR^(c3)C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)R^(d3) NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3) S(O)R^(b3),NR^(c3) S(O)₂R^(b3), NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); R⁵ and R⁶ areeach H; R^(Z) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4)NR^(c4)C(═NR^(e4))NR^(c4)R^(d4) NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),C(═NR^(e4))NR^(c4)R^(d4) NR^(c4)C(═NR^(e4))NR^(c4)R^(d4) NR^(c4)R^(d4)NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); eachR^(a), R^(b), R^(c), R^(d), R^(a2), R^(b2), R^(c2), R^(d2), R^(a3),R^(b3), R^(c3), R^(d3), R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5); or any R^(c) and R^(d) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5); or any R^(c2) and R^(d2) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl,C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5); or any R^(c3) and R^(d3) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5); or any R^(c4) and R^(d4) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5); each R^(a1), R^(b1), R^(c1), R^(d1) is independentlyselected from H and C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from halo, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5); each R^(a5), R^(b5), R^(c5), and R^(d5) isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy; and each R^(e), R^(e1), R^(e2), R^(e3),R^(e4), and R^(e5) is independently selected from H, C₁₋₄ alkyl, and CN;m is 0, 1, or 2; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; and q is 0or
 1. 2-3. (canceled)
 4. The compound of claim 1 having Formula IIIa:

or a pharmaceutically acceptable salt thereof, wherein: wherein each R²is substituted on any ring-forming carbon atom of the azetidine ringdepicted in Formula IIIa except the ring-forming carbon atom to whichR^(Z) is bonded.
 5. The compound of claim 4, or a pharmaceuticallyacceptable salt thereof, having Formula IVa:


6. The compound of claim 1 having Formula Va:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein q is
 0. 8. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein q is
 1. 9. (canceled)
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein n is
 0. 11. (canceled)12. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein ring C is phenyl.
 13. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein ring C is monocyclic5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatomsselected from N, O, and S.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein ring C is phenyl,pyridyl, piperazinyl, pyrazinyl, pyrimidinyl, or pyrazolyl.
 15. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein ring C is phenyl, pyridyl, piperazinyl, pyrazinyl, or pyrazolyl.16. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁴ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, CN, NR^(c3)R^(d3), C(O)OR^(a3), orC(O)NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)R^(d3),NR^(c3)C(O)R^(b3) NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3). 17.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, CN, or C(O)NR^(c3)R^(d3), wherein said C₁₋₆ alkyl and4-10 membered heterocycloalkyl are each optionally substituted with 1,2, 3, or 4 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)C(═NR^(e3))NR^(c3)R^(d3) NR^(c3)R^(d3)NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3), NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).
 18. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR³ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN,OR^(a2), and C(O)NR^(c2)R^(d2), wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)R^(d2) NR^(c2)C(O)R^(b2)NR^(c2)C(O)OR^(a2) NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2)NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).
 19. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR³ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN,OR^(a2), and C(O)NR^(c2)R^(d2).
 20. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein p is
 0. 21. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein p is
 1. 22. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein p is
 2. 23. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein m is
 0. 24. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein m is
 1. 25. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(Z) is C₁₋₄ alkyl or C₆₋₁₀ aryl-C₁₋₄alkyl-, wherein said C₁₋₄ alkyl and C₆₋₁₀ aryl-C₁₋₄ alkyl- are eachoptionally substituted by halo, CN, or OR^(a4).
 26. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R^(Z) isC₁₋₄ alkyl.
 27. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(Z) is C₁₋₄ alkyl substituted by CNor methoxy.
 28. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(Z) is C₆₋₁₀ aryl-C₁₋₄alkyl-substituted by fluoro.
 29. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(Z) is methyl,cyanomethyl, methoxymethyl, or 4-fluorophenylmethyl.
 30. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R^(Z) isC₁₋₄ alkyl substituted by CN.
 31. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(Z) is cyanomethyl.32. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(Z) is H.
 33. The compound of claim 1, or apharmaceutically acceptable salt thereof, having a trans configurationwith respect to the di-substituted cyclopropyl group depicted in FormulaII.
 34. The compound of claim 1, wherein the compound is selected from:3-Fluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile;3,5-Difluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile;2,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;2-Methyl-6-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]nicotinonitrile;N-Ethyl-5-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)pyrazine-2-carboxamide;3,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;2,6-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;2,3-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;2-Chloro-5-fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}-azetidin-1-yl)benzamide;3-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;2-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;2-Fluoro-N-isopropyl-5-methyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl})-azetidin-1-yl)benzamide;N-Isopropyl-2-methoxy-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;3-Chloro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;5-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide;N-({1-[6-(4-Methylpiperazin-1-yl)pyrimidin-4-yl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine;andtrans-N-{[1-(1-Methyl-1H-pyrazol-4-yl)azetidin-3-yl]methyl}-2-phenylcyclopropanamine;or a pharmaceutically acceptable salt of any of the aforementioned. 35.(canceled)
 36. A pharmaceutical composition comprising a compound ofclaim 1, or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 37. A method of inhibiting LSD1comprising contacting a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, with said LSD1.
 38. A method of treating adisease comprising administering to a patient a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein said disease is cancer.
 39. The methodof claim 38 wherein said cancer is a hematological cancer.
 40. Themethod of claim 39 wherein said hematological cancer is selected fromacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma, Hodgkin lymphoma,primary myelofibrosis (PMF), polycythemia vera (PV), essentialthrombocytosis (ET)), myelodysplasia syndrome (MDS), or multiplemyeloma.
 41. The method of claim 38 wherein said cancer is a sarcoma,lung cancer, gastrointestinal cancer, genitourinary tract cancer, livercancer, bone cancer, nervous system cancer, gynecological cancer, orskin cancer.
 42. A method of treating a disease comprising administeringto a patient a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof, wherein said diseaseis a viral disease or a beta-globinopathy.
 43. The method of claim 40,wherein said hematological cancer is myelodysplasia syndrome.
 44. Themethod of claim 40, wherein said hematological cancer is acutemyelogenous leukemia.
 45. The method of claim 40, wherein saidhematological cancer is primary myelofibrosis.
 46. The method of claim41, wherein said lung cancer is undifferentiated small cell lung cancer.47. The method of claim 38, wherein said cancer is Ewing's sarcoma.